3491

CYR61

cysteine-rich, angiogenic inducer, 61;CYR61;cysteine-rich, angiogenic inducer, 61

CCN family member 1|IBP-10|IGF-binding protein 10|IGFBP-10|cysteine-rich heparin-binding protein 61|cysteine-rich, anigogenic inducer, 61|insulin-like growth factor-binding protein 10|protein CYR61

1p22.3

protein-coding

AIM: To investigate the expression of cysteine-rich61 (Cyr61), connective tissue growth factor (CTGF) and nephroblastoma overexpressed gene (Nov) in hepatocellular carcinoma (HCC), and to evaluate the relationship between Cyr61, CTGF and Nov genes expression with invasion and metastasis of HCC. METHODS: Thirty-one HCC specimens were divided into small hepatocellular carcinoma (SHCC), nodular hepatocellular carcinoma (NHCC), solitary large hepatocellular carcinoma (SLHCC) according to their diameter and number of nodes. Reverse transcription polymerse chain reaction (RT-PCR) was used to detect the mRNA expression levels of Cyr61, CTGF and Nov genes in 31 resected specimens of hepatocellular carcinoma and para-cancerous normal liver tissues semi-quantitatively and the relation between their expression levels and clinical pathological parameters were compared. RESULTS: The expressions of Cyr61 and CTGF mRNA in carcinoma tissues were significantly higher than those in para-cancerous normal liver tissues (P<0.01). The expressions of Cyr61 and CTGF mRNA in HCC with venous invasion were higher than those in HCC without venous invasion. CTGF expression in HCC Edmondson's grade III-IV was significantly higher than that in HCC Edmondson's grade I-II (P = 0.022). There was no obvious correlation between Nov mRNA and clinical-pathological features. Compared to NHCC, SLHCC had better cell differentiation, easier capsule formation, less microscopic venous invasion, milder liver cirrhosis. The expressions of Cyr61 and CTGF mRNA in NHCC were significantly higher than those in SLHCC and SHCC. CONCLUSION: Cyr61 and CTGF genes may play an important role in hepatocellular carcinogenesis and correlate with recurrence and metastasis of hepatocellular carcinoma. SLHCC has better biological behaviors than NHCC.

Cysteine-rich protein 61 (Cyr61) is a member of a family of growth factor-inducible, immediate-early genes. In this report, the authors measured the expression of Cyr61 mRNA in 94 human lung tumors and their normal matched lung samples. The Cyr61 mRNA levels were quantified by real time reverse transcriptase-polymerase chain reaction and calculated as a tumor/normal Cyr61 mRNA ratio in each case. Compared with normal matched lung tissues, expression of Cyr61 was decreased in 74 of 94 (79 percent) lung tumors. Differences in distribution of patient characteristics, such as gender, age, tumor size, and pathological diagnosis, between high or low Cyr61 expressing groups were not statistically significant. However, differences in distribution of clinical stage between high or low Cyr61 expressing groups was statistically significant; that is, the Cyr61 low expressor group was clinically more advanced than the Cyr61 high expressor group (p = 0.046). Furthermore, Cyr61 levels of the patients with N0 and N1 diseases were significantly higher than the expression in the N2 patients (p = 0.047). The 3-year survival between the Cyr61 very low tumor expressor group compared to matched normal lung (39 patients) and the higher Cyr61 expressor group (52 patients) was statistically significant (59 versus 91 percent; p = 0.05). Taken together, Cyr61 appears to guard against metastatic disease because low expression is associated with more advanced disease; and therefore, expression levels of Cyr61 correlate with the prognosis of lung cancer.

metastatic progression of melanoma is associated with overexpression and activity of cAMP-response element-binding protein (CREB). However, the mechanism by which CREB contributes to tumor progression and metastasis remains unclear. Here, we demonstrate that stably silencing CREB expression in two human metastatic melanoma cell lines, A375SM and C8161-c9, suppresses tumor growth and experimental metastasis. Analysis of cDNA microarrays revealed that CREB silencing leads to increased expression of cysteine-rich protein 61 (CCN1/CYR61) known to mediate adhesion, chemostasis, survival, and angiogenesis. Promoter analysis and chromatin immunoprecipitation assays demonstrated that CREB acts as a negative regulator of CCN1/CYR61 transcription by directly binding to its promoter. Re-expression of CREB in CREB-silenced cells rescued the low CCN1/CYR61 expression phenotype. CCN1/CYR61 overexpression resulted in reduced tumor growth and metastasis and inhibited the activity of matrix metalloproteinase-2. Furthermore, its overexpression decreased melanoma cell motility and invasion through Matrigel, which was abrogated by silencing CCN1/CYR61 in low metastatic melanoma cells. Moreover, a significant decrease in angiogenesis as well as an increase in apoptosis was seen in tumors overexpressing CCN1/CYR61. Our results demonstrate that CREB promotes melanoma growth and metastasis by down-regulating CCN1/CYR61 expression, which acts as a suppressor of melanoma cell motility, invasion and angiogenesis.

BACKGROUND: Cysteine-rich protein 61 (Cyr61) plays a role as a tumor suppressor in non-small cell lung cancer (NSCLC). Cyr61 and WISP-3 have a very significant sequence homology, belonging to the same CCN gene family. The aim of this study is to investigate the expressions of Cyr61 and WISP-3 in NSCLC, and explore the relationship between their expressions and tumor's clinicopathological characteristics. METHODS: The expressions of Cyr61 and WISP-3 were detected in 54 cases with primary NSCLC and their corresponding normal lung tissues in control group by immunohistochemical staining (SP), and the clinical data were analyzed. RESULTS: Down-regulation of Cyr61 and up-regulation of WISP-3 were both found in lung cancer tissue compared with the corresponding normal lung tissue (both P < 0.001); The expression of Cyr61 was negatively correlated with the expression of WISP-3 (r=-0.395, P=0.003); Cyr61 expression levels was closely correlated with tumor grade, tumor type, clinical stage, family history, smoking and metastasis (P < 0.05). Also, WISP-3 was closely correlated with tumor grade, clinical stage and age (P < 0.05). CONCLUSIONS: The expressions of Cyr61 and/or WISP-3 may be important biological markers in reflecting the progression, biological behaviors, metastatic potential and prognosis of NSCLC.

Overexpressed cysteine-rich protein 61 (Cyr61) is believed to enhance osteosarcoma (OS) cell metastasis, but the mechanism of Cyr61 overexpression in OS is not clear so far. In this study 33 OS samples were analyzed by immunostaining and focused on two parts: the correlation between overexpression of Cyr61 and OS metastasis; the mechanism of regulating Cyr61 expression in OS. Twenty-five out of 33 cases (75.76 %) with metastasis showed high expression of Cyr61. Furthermore, Cyr61 expression in Saos-2 cells was reduced by siRNA, and lower expression of Cyr61 in Saos-2 cell resulted in a cell migration deficiency and had no effect on cell proliferation. Particularly, Cyr61 expression was significantly increased in Saos-2 cells in response to different dosages of transforming growth factor beta (TGF-beta), indicating that the expression of Cyr61 is TGF-beta dependent. A transwell assay showed that Saos-2 cells stimulated with TGF-beta had a greater capacity for migration than the control cells. The p38 MAPK-specific inhibitor SB203580 was able to reduce Cyr61 expression and inhibit the migration of Saos-2 cells stimulated with TGF-beta. These results obtained provide new evidence that overexpressed Cyr61 plays a key role in the metastasis of OS cells and Cyr61 is a potential target downstream of TGF-beta/p38 MAPK to regulate cell migration.

Cyr61 has been reported to participate in the development and progression of various cancers; however, its role in prostate cancer (PCa) still remains poorly understood. In this study, we explored the function of Cyr61 in a series of malignant PCa cell lines, including LnCap, Du145, and PC3. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and crystal violet assays demonstrated that Cyr61 was essential for the proliferation of PCa cells. Soft agar assay and xenograft analysis showed that downregulation of Cyr61 suppressed the tumorigenicity of Du145 cells both in vitro and in vivo. Either silencing the cellular Cyr61 by RNA interference or neutralising the endogenous Cyr61 by antibody inhibited the migration of Du145 cells. In contrast, purified protein of Cyr61 promoted the migration of LnCap cells in a dose-dependent manner. These results suggested that Cyr61 was involved in the migration of PCa cells. We also observed the accumulation of mature focal adhesion complexes associated with the impaired migration through Cyr61 downregulation. Also, further studies showed that Cyr61 regulated the level of activated Rac1 as well as its downstream targets, including phosphorylated JNK, E-cadherin, and p27(kip1), which are key molecules involved in cell growth, migration, and invasion. The in vivo mouse tail vein injection experiment revealed that Cyr61 affected the metastatic capacity of Du145 cells, suggesting that Cyr61 was required for prostate tumour metastasis. Altogether, our results demonstrated that Cyr61 played an important role in the tumorigenicity and metastasis of PCa cells, which will benefit the development of therapeutic strategy for PCas.

OBJECTIVE: The objective of this study was to examine the expression of cysteine-rich protein 61 (Cyr61) in the distant metastatic tumor cells of human primary salivary adenoid cystic carcinoma (SACC) and its relationship with tumor angiogensis and metastasis. STUDY DESIGN: The experimental group comprised 35 paraffin-embedded tumor specimens of distant metastasis from primary SACC, with their corresponding primary tumor tissues and matched normal salivary gland tissues used as the control groups. Immunohistochemical staining was used to detect the expression of Cyr61 and vascular endothelial growth factor in the experimental and control groups. Vascular endothelial cells were highlighted by the anti-CD34 antibody, and the Weidner method was used to quantify microvessel density (MVD). RESULTS: Cyr61 was overexpressed in distant metastatic tumor cells of primary SACC. Positive expression of Cyr61 and vascular endothelial growth factor (VEGF) progressively increased in normal salivary gland tissues, primary tumor tissues, and tumor tissues of distant metastasis (P < .05). Compared with primary tumor tissues, Cyr61 expression and VEGF expression showed significant increase in tumor tissues of distant metastasis (P < .05). Cyr61 expression significantly correlated with VEGF expression and MVD (P < .05). CONCLUSIONS: Cyr61 appeared to have a significant association with tumor angiogenesis and metastasis in SACC and may be an important target in tumor antiangiogenesis therapy.